The blood-brain barrier plays a vital role in the protection of the central nervous system. It is composed of endothelial cells with tight-junctions to limit the penetration of many endogenous and exogenous compounds, particularly hydrophilic xenobiotics. Nerve agents and pesticides are groups of compounds with high penetration potential into the central nervous system. However, oxime type antidotes are known to penetrate blood-brain barrier only in low concentration. The aim of presented study is to describe the pharmacokinetic profile of oxime K027 a novel antidote candidate. The main focus is on penetration of tested substance into the selected brain regions following time-dependent manner. The maximum concentration of the oxime K027 was attaining 15 and 30 min after i.m. application in plasma and brain tissue, respectively. The perfused brain tissue concentration was relatively high (10(-7) M order of magnitude) and depending on the brain region it was constant 15-60 min after application. The highest concentration was found in the frontal cortex 15 min after application while the lowest measured concentration was determined in the basal ganglia. This study showed that oxime K027 is able to achieve high concentration level in perfused brain tissue relatively quickly, but also demonstrated rapid clearance from the central nervous system. These results are probably due to low overall uptake of oxime K027 into the brain.

• MeSH
• časové faktory MeSH
• centrální nervový systém účinky léků   metabolismus   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• mozek účinky léků   metabolismus   MeSH
• oximy metabolismus   farmakokinetika   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny metabolismus   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• oximy MeSH
• pyridinové sloučeniny MeSH

The toxic effect of organophosphates is attributed to irreversible inhibition of acetylcholinesterase (AChE; EC 3.1.1.7), the enzyme that hydrolyses the neurotransmitter acetylcholine. Inhibition potency in vivo of one of the most toxic nerve agents--Russian VX (RVX;N,N-diethyl-2-[methyl-(2-methylpropoxy)phosphoryl]sulfanylethanamine) (1 x LD(50) dose administered intramuscularly, i.m.) was studied in rats. AChE in blood was inhibited by 50%, 3 min after i.m. RVX. Butylcholinesterase (BChE; EC 3.1.1.8) in plasma was inhibited less rapidly and only by 10-20%, 20 min after RVX. AChE and BChE activities in diaphragm were reduced only 35% and 15% at 30 min. While AChE and BChE activities were reduced only about 20% and 15%, respectively, the decline in activity was rapid, occurring within 3 min. These findings indicate that RVX most potently inhibits ChE outside the central nervous system.

• MeSH
• acetylcholinesterasa krev   MeSH
• bránice účinky léků   enzymologie   MeSH
• časové faktory MeSH
• chování zvířat účinky léků   MeSH
• játra účinky léků   enzymologie   MeSH
• krysa rodu Rattus MeSH
• LD50 MeSH
• mozek účinky léků   enzymologie   MeSH
• organothiofosforové sloučeniny toxicita   MeSH
• potkani Wistar MeSH
• tkáňová distribuce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• organothiofosforové sloučeniny MeSH
• S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate MeSH Prohlížeč